Aminomethanobenzazocine intermediates

ABSTRACT

N-Alkylated-8-aminated-2,6-methano-3-benzazocines, useful as strong analgesics, are prepared by one route comprising reduction of 8-nitro intermediates or by another route comprising Birch type reduction of 8-methoxy intermediates followed by dehydration-rearrangement of the oximes of the resulting 8-oxo intermediates.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of our copending application Ser. No.507,965, filed Sept. 20, 1974 now U.S. Pat. No. 3,957,973.

SUMMARY OF THE INVENTION

This invention relates to intermediates and processes useful in thepreparation N-alkylated-8-aminated-2,6-methano-3-benzazocines, which areuseful as strong analgesics and which are more particularly defined as1,2,3,4,5,6-hexahydro-3-Q-8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineshaving the formula ##STR1## wherein: Q is propyl, isobutyl, neopentyl,allyl, 2-methyl-2-propenyl, 2-chloro-2-propenyl,cis-3-chloro-2-propenyl, cis-3-chloro-2-butenyl,trans-3-chloro-2-butenyl, propargyl, cyclopropylmethyl or(2,2-dichlorocyclopropyl)methyl;

R is hydrogen or methyl;

R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, benzyl or cyclopropylmethyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl;

And acid addition salts thereof.

In addition to being useful as strong analgesics some of the compoundsof Formula I are also useful as intermediates for preparing othercompounds of Formula I and are thus one related intermediate aspect ofthe invention.

Another related intermediate aspect of the invention sought to bepatented is1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinehaving the formula ##STR2## wherein: Q' is hydrogen, benzyl, propyl,isobutyl, neopentyl, allyl, 2-methyl-2-propenyl, 2-chloro-2-propenyl,cis-3-chloro-2-propenyl, cis-3-chloro-2-butenyl,trans-3-chloro-2-butenyl, propargyl, cyclopropylmethyl or(2,2-dichlorocyclopropyl)methyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl;

or an acid addition salt thereof.

Still another related intermediate aspect of the invention sought to bepatented is1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-oxo-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinehaving the formula ##STR3## wherein: Q' is hydrogen, benzyl, propyl,isobutyl, neopentyl, allyl, 2-methyl-2-propenyl, 2-chloro-2-propenyl,cis-3-chloro-2-propenyl, cis-3-chloro-2-butenyl,trans-3-chloro-2-butenyl, propargyl, cyclopropylmethyl or(2,2-dichlorocyclopropyl)methyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl;

or an acid addition salt thereof.

One related process aspect of the invention sought to be patented is theprocess which comprises reducing1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula II by a method effective in reducing 8-nitro to 8-aminowithout otherwise reducing or transforming the molecule to produce1,2,3,4,5,6-hexahydro-3-Q'-8-amino-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinewherein:

Q' is hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl,2-methyl-2-propenyl, 2-chloro-2-propenyl, cis-3-chloro-2-propenyl,cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl.

Another related process aspect of the invention sought to be patented isthe process which comprises nitrating1,2,3,4,5,6-hexahydro-3-Q'-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineto produce1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula II wherein:

Q' is hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl,2-methyl-2-propenyl, 2-chloro-2-propenyl, cis-3-chloro-2-propenyl,cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,cyclopropylmethyl of (2,2-dichlorocyclopropyl)methyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl.

Still another related process aspect of the invention sought to bepatented is the process which comprises reducing1,2,3,4,5,6-hexahydro-3-Q'-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineby a reduction of the Birch type to produce1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-oxo-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula III wherein:

Q' is hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl,2-methyl-2-propenyl, 2-chloro-2-propenyl, cis-3-chloro-2-propenyl,cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl.

One intermediate aspect of the invention sought to be patented is1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-hydroxyimino-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinehaving the formula ##STR4## wherein: Q' is hydrogen, benzyl, propyl,isobutyl, neopentyl, allyl, 2-methyl-2-propenyl, 2-chloro-2-propenyl,cis-3-chloro-2-propenyl, cis-3-chloro-2-butenyl,trans-3-chloro-2-butenyl, propargyl, cyclopropylmethyl or(2,2-dichlorocyclopropyl)methyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl;

or an acid addition salt thereof.

Another intermediate aspect of the invention sought to be patented is1,2,3,4,5,6-hexahydro-3-Q°-8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine having the formula ##STR5## wherein: Q° ishydrogen or benzyl;

R is hydrogen or methyl;

R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, benzyl or cyclopropylmethyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl;

or an acid addition salt thereof.

Still another intermediate aspect of the invention sought to be patentedis1,2,3,4,5,6-hexahydro-3-Q"-8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinehaving the formula ##STR6## wherein: Q" is formyl, acetyl or Q* whereinQ* is propionyl, isobutyryl, pivaloyl, acryloyl, 2-methylacryloyl,2-chloroacryloyl, cis-3-chloroacryloyl, cis-3-chlorocrotonyl,trans-3-chlorocrotonoyl, propiolyl, cyclopropanecarbonyl or2,2-dichlorocyclopropanecarbonyl;

R is hydrogen or methyl;

R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, benzyl or cyclopropylmethyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl;

or an acid addition salt thereof.

Yet another intermediate aspect of the invention sought to be patentedis1,2,3,4,5,6-hexahydro-3-Q"-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinehaving the formula ##STR7## wherein: Q" is formyl, acetyl or Q* whereinQ* is propionyl, isobutyryl, pivaloyl, acryloyl, 2-methylacryloyl,2-chloroacryloyl, cis-3-chloroacryloyl, cis-3-chlorocrotonoyl,trans-3-chlorocrotonoyl, propiolyl, cyclopropanecarbonyl or2,2-dichlorocyclopropanecarbonyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl.

Even another intermediate aspect of the invention sought to be patentedis1,2,3,4,5,6-hexahydro-3-Q'-8-RR"N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinehaving the formula ##STR8## wherein: Q' is hydrogen, benzyl, propyl,isobutyl, neopentyl, allyl, 2-methyl-2-propenyl, 2-chloro-2-propenyl,cis-3-chloro-2-propenyl, cis-3-chloro-2-butenyl,trans-3-chloro-2-butenyl, propargyl, cyclopropylmethyl or(2,2-dichlorocyclopropyl)methyl;

R is hydrogen or methyl;

R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl orcyclopropanecarbonyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl;

or an acid addition salt thereof.

Finally another intermediate aspect of the invention sought to bepatented is1,2,3,4,5,6-hexahydro-3-Q"-8-RR"N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinehaving the formula ##STR9## wherein: Q" is formyl, acetyl or Q* whereinQ* is propionyl, isobutyryl, pivaloyl, acryloyl, 2-methylacryloyl,2-chloroacryloyl, cis-3-chloroacryloyl, cis-3-chlorocrotonoyl,trans-3-chlorocrotonoyl, propiolyl, cyclopropanecarbonyl or2,2-dichlorocyclopropanecarbonyl;

R is hydrogen or methyl;

R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl orcyclopropanecarbonyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl.

The compounds of Formulas II-IX are useful as intermediates forpreparing compounds of Formula I.

A process aspect of the invention sought to be patented is the processwhich comprises dehydrating and rearranging1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-hydroxyimino-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula IV to produce1,2,3,4,5,6-hexahydro-3-Q'-8-amino-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinewherein:

Q' is hydrogen, benzyl, propyl, isobutyl, neopentyl, allyl,2-methyl-2-propenyl, 2-chloro-2-propenyl, cis-3-chloro-2-propenyl,cis-3-chloro-2-butenyl, trans-3-chloro-2-butenyl, propargyl,cyclopropylmethyl or (2,2-dichlorocyclopropyl)methyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl.

Another process aspect of the invention sought to be patented is theprocess which comprises selectively hydrolyzing1,2,3,4,5,6-hexahydro-3-Q"-8-RR"N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula IX by a method effective in removing R" without removing Q"to produce1,2,3,4,5,6-hexahydro-3-Q"-8-RHN-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinewherein:

Q" is formyl, acetyl or Q* wherein Q* is propionyl, isobutyryl,pivaloyl, acryloyl, 2-methylacryloyl, 2-chloroacryloyl,cis-3-chloroacryloyl, cis-3-chlorocrotonoyl, trans-3-chlorocrotonoyl,propiolyl, cyclopropanecarbonyl or 2,2-dichlorocyclopropanecarbonyl;

R is hydrogen or methyl;

R" is formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl orcyclopropanecarbonyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl.

Still another process aspect of the invention sought to be patented isthe process which comprises reducing1,2,3,4,5,6-hexahydro-3-Q"-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula VII by a method effective in reducing 8-nitro to 8-aminowithout otherwise reducing or transforming the molecule to produce1,2,3,4,5,6-hexahydro-3-Q"-8-amino-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinewherein:

Q" is formyl, acetyl or Q* wherein Q* is propionyl, isobutyryl,pivaloyl, acryloyl, 2-methylacryloyl, 2-chloroacryloyl,cis-3-chloroacryloyl, cis-3-chlorocrotonoyl, trans-3-chlorocrotonoyl,propiolyl, cyclopropanecarbonyl or 2,2-dichlorocyclopropanecarbonyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl.

Yet another process aspect of the invention sought to be patented is theprocess which comprises reducing 1,2,3,4,5,6-hexahydro-3-Q*-8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine of Formula VI bya method effective in reducing 3-Q* to 3-Q without otherwise reducing ortransforming the molecule to produce1,2,3,4,5,6-hexahydro-3-Q-8-RR'-N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula I wherein:

Q is propyl, isobutyl, neopentyl, allyl, 2-methyl-2-propenyl,2-chloro-2-propenyl, cis-3-chloro-2-propenyl, cis-3-chloro-2-butenyl,trans-3-chloro-2-butenyl, propargyl, cyclopropylmethyl or(2,2-dichlorocyclopropyl)methyl;

Q* is propionyl, isobutyryl, pivaloyl, acryloyl, 2-methylacryloyl,2-chloroacryloyl, cis-3-chloroacryloyl, cis-3-chlorocrotonoyl,trans-3-chlorocrotonoyl, propiolyl, cyclopropanecarbonyl or2,2-dichlorocyclopropanecarbonyl;

R is hydrogen or methyl;

R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, benzyl or cyclopropylmethyl;

X is hydrogen, methyl or ethyl;

Y is hydrogen, methyl, ethyl, propyl, allyl or phenyl;

Z is hydrogen, methyl, ethyl or hydroxy; and

Z' is hydrogen, methyl or ethyl.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formulas I-IX can each exist as one or the otheroptical isomer or a mixture thereof. The features ##STR10## and C..Z'represent bonds oriented below the plane of the page if the plane of thetetralin moiety is considered to be in the plane of the page. When Z ismethyl, ethyl or hydroxy, it is referred to as equatorial (eq) withrespect to the tetralin moiety and trans with respect to Y. When Z ishydroxy, the 11-carbon atom is SR in chirality and the compound is inthe α-series of benzomorphans as designated by May and coworkers (seeNathan B. Eddy and Everette L. May, Synthetic Analgesics, Part IIB ofParts IIA and IIB, Pergamon Press, Oxford, 1966, pp. 117-137). When Z'is methyl or ethyl, it is referred to as axial (ax) with respect to thetetralin moiety and cis with respect to Y. When X is methyl or ethyl, itis referred to as equatorial with respect to the hexahydrobenzazocinemoiety and trans with respect to Y.

The compounds of Formulas I-VI and VIII are amino bases and react withorganic and inorganic acids to form acid addition salts. Due to thepresence of the basic amino grouping, the free base forms represented bythe formulas react with organic and inorganic acids to form acidaddition salts. The acid addition salt forms are prepared from anyorganic or inorganic acid. They are obtained in conventional fashion,for instance either by direct mixing of the base with the acid or, whenthis is not appropriate, by dissolving either or both of the base andthe acid separately in water or an organic solvent and mixing the twosolutions, or by dissolving both the base and the acid together in asolvent. The resulting acid addition salt is isolated by filtration, ifit is insoluble in the reaction medium, or by evaporation of thereaction medium to leave the acid addition salt as a residue. The acidmoieties or anions in these salt forms are in themselves neither novelnor critical and therefore can be any acid anion or acid-like substancecapable of salt formation with the base.

Representative acids for the formation of the acid-addition saltsinclude formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaricacid, succinic acid, succinamic acid, tannic acid, glutamic acid,tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid,glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin,benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid,anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, pamoic acid,3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid,3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonicacid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid,acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid,hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoricacid, arsenic acid, and the like. All of the acid addition salts areuseful as sources of the free bases by reaction with a stronger base.Thus, if one or more characteristics such as solubility, molecularweight, physical appearance, toxicity or the like or a given base oracid addition salt thereof render that form unsuitable for the purposeat hand, it can be readily converted to another, more suitable form. Forpharmaceutical purposes, acid addition salts of relatively non-toxic,pharmaceutically-acceptable acids, for example hydrochloric acid, lacticacid, tartaric acid, and the like, are of course employed. Either thefree bases or the acid addition salts thereof may crystallize ascrystalline solvates with solvent of crystallization in integral orfractional amounts, for example, as the hydrate sesquihydrate orethanolate.

The manner and process of making and using the invention and the bestmode of carrying it out will now be described so as to enable any personskilled in the art to which it pertains to make and use it.

The process which comprises reducing1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula II is carried out by any method effective in reducing 8-nitroto 8-amino without otherwise reducing or transforming the molecule, forexample, by the use of iron and aqueous hydrochloric acid. A cosolvent,for example, ethanol can be used. A buffering agent, for example, sodiumacetate, can also be used. The rate of the reduction can be controlledby heating or cooling. The process which comprises reducing1,2,3,4,5,6-hexahydro-3-Q"-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula VII is carried out similarly.

The process which comprises dehydrating and rearranging1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-hydroxyimino-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula IV is effectively an aromatization process and is carried outby any method effective in dehydrating the oxime without otherwisedehydrating or transforming the molecule, for example, by the use ofhydrochloric acid and acetic anhydride. A solvent, for example, aceticacid, can be used. The rate of the aromatization can be controlled byheating or cooling. The use of hydrochloric acid and acetic anhydride onthe compounds of Formula IV produces the corresponding compounds ofFormula VIII wherein R is hydrogen and R" is acetyl and thecorresponding compounds of Formula IX wherein R is hydrogen and Q" andR" are both acetyl, which can be isolated or can be hydrolyzed withoutisolation to remove acetyl.

The 8-nitro reductions and the 8-hydroxyiminodehydration-rearrangement-hydrolysis sequence are alternative processesand produce only the corresponding compounds of Formulas I, V and VIwherein R and R' are both hydrogen, which can be used as intermediatesfor preparing the remaining compounds of Formulas I, V and VI wherein Ris methyl and R' is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, benzyl or cyclopropylmethyl, which are prepared either byalkylation or by an acylation-reduction sequence. The alkylation isaccomplished using, for example, dimethyl sulfate, ethyl iodide, propylbromide, isopropyl bromide, butyl methanesulfonate, isobutyl bromide,sec-butyl bromide, benzyl chloride or cyclopropylmethyl bromide.Dimethylation is preferably accomplished by catalytic hydrogenativemethylation using formaldehyde and palladium-on-carbon as catalyst or,alternatively, by reductive methylation using formaldehyde and formicacid. Monobenzylation is preferably accomplished by reductivebenzylation using benzaldehyde and sodium borohydride. The acylationstep of the acylation reduction sequence affords the correspondingcompounds of Formulas VIII and IX and is accomplished using, forexample, formic-acetic anhydride, acetic anhydride, propionic anhydride,butyric anhydride, isobutyryl chloride, benzoyl chloride orcyclopropanecarbonyl chloride. The reduction step of theacylation-reduction sequence is accomplished using, for example,diborane or lithium aluminum hydride and results in the simultaneousreduction of Q* in the compounds of Formula IX to the corresponding Q inthe compounds of Formula I.

A third alternative process for preparing the compounds of Formula I isthe process which comprises reducing the corresponding1,2,3,4,5,6-hexahydro-3-Q*-8-RR'N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula VI, which is also accomplished using, for example, lithiumaluminum hydride.

Producing the desired combination of Q, R and R' in the compounds ofFormula I may require the use of protecting groups during N-alkylationor N-acylation. Benzyl is such a protecting group in the compounds ofFormula VIII wherein Q' is benzyl and can be removed, for example, bycatalytic hydrogenation using palladium as catalyst. Formyl and acetylare such protecting groups in the compounds of Formula VI wherein Q" isformyl or acetyl and can be removed, for example, by hydrolysis.

In the compounds of Formula IX R" is selectively removed withoutremoving Q" in the process which comprises selectively hydrolyzing1,2,3,4,5,6-hexahydro-3-Q"-8-RR"N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula IX, which is accomplished using, for example, dilutehydrochloric acid. The rate of the selective hydrolysis can becontrolled by heating or cooling.

The process which comprises nitrating1,2,3,4,5,6-hexahydro-3-Q'-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineto produce1,2,3,4,5,6-hexahydro-3-Q'-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula II is carried out by any method effective in substitutingnitro for hydrogen at the 8-position of the aromatic ring withoutotherwise transforming the molecule, for example, by the use of nitricacid. A solvent is preferably used, for example, acetic acid. The rateof the nitration can be controlled by heating or cooling.1,2,3,4,5,6-Hexahydro-3-Q"-8-nitro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula VII is similarly obtained by nitrating1,2,3,4,5,6-hexahydro-3-Q"-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine.

The process which comprises reducing1,2,3,4,5,6-hexahydro-3-Q'-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineis carried out by a reduction of the Birch type (The Merck Index, EighthEdition, Merck & Co., Rahway, N.J., 1968, p. 1146) using, for example,sodium and liquid ammonia. A cosolvent, for example, a mixture oftetrahydrofuran and isopropyl alcohol can be used.1,2,3,4,5,6,7,10-Octahydro-3-Q'-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineis the immediate product and is easily hydrolyzed using, for example,dilute hydrochloric acid to produce1,2,3,4,5,6,7,8,9,10-decahydro-3-Q'-8-oxo-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineof Formula III. If Q' is benzylic or allylic, it is removed by thereduction, but can be replaced by one of the methods described below.

The compounds of Formula IV are prepared from the correspondingcompounds of Formula III using hydroxylamine or an acid addition saltthereof, for example, hydroxylamine hydrochloride.

In the compounds of Formulas VI, VII and IX Q" is introduced byacylation of the corresponding compounds of Formula V wherein Q° ishydrogen, the compounds of Formula II wherein Q' is hydrogen and thecompounds of Formula VIII wherein Q' is hydrogen, respectively, using,for example, formic-acetic anhydride, acetic anhydride, propionylchloride, isobutyryl chloride, pivaloyl chloride, 2-methylacryloylchloride, 2-chloroacryloyl chloride, cis-3-chloroacryloyl chloride,cis-3-chlorocrotonoyl chloride, trans-3-chlorocrotonoyl chloride,propiolyl chloride, cyclopropanecarbonyl chloride or2,2-dichlorocyclopropanecarbonyl chloride. Alternatively, Q" is builtinto the compounds of Formula VII by first acylating the corresponding1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocine andthen nitrating the resulting1,2,3,4,5,6-hexahydro-3-Q"-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocineas described above.

Thus, Q can be built into the compounds of Formula I by anacylation-reduction sequence through the corresponding Q*, which appearsin the compounds of Formulas VI, VII and IX, as described above, or,alternatively, by alkylation in the corresponding compounds of FormulasII, III and VIII wherein Q' is hydrogen, the corresponding1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinesprior to 8-nitration or the corresponding1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinesprior to the Birch reduction using, for example, propyl bromide,isobutyl bromide, neopentyl bromide, allyl chloride, 2-methyl-2-propenylchloride, 2-chloro-2-propenyl chloride, cis-3-chloro-2-propenylchloride, cis-3-chloro-2-butenyl chloride, trans-3-chloro-2-butenylchloride, propargyl bromide, cyclopropylmethyl bromide or(2,2-dichlorocyclopropyl)methyl bromide.

Some of the1,2,3,4,5,6-hexahydro-3-Q'-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines,1,2,3,4,5,6-hexahydro-3-Q'-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines,1,2,3,4,5,6-hexahydro-3-Q"-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinesand1,2,3,4,5,6-hexahydro-3-Q"-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinesare known; those which are not known are prepared from the corresponding1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines and1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinesby the methods described above. Some of the1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines and1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methoxy-3-benzazocinesare known; those which are not known are prepared, for example, from thecorresponding1,2,3,4,5,6-hexahydro-3-methyl-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinesand1,2,3,4,5,6-hexahydro-3-methyl-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines,for example, by cyanogenation with cyanogen bromide followed byhydrolysis of the resulting1,2,3,4,5,6-hexahydro-3-cyano-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines and 1,2,3,4,5,6-hexahydro-3-cyano- 8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines. Those1,2,3,4,5,6-hexahydro-3-methyl-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines which are not known are preparedfrom the corresponding1,2,3,4,5,6-hexahydro-3-methyl-8-hydroxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinesby O-methylation using, for example, diazomethane.

The various combinations of the X-, Y-, Z- and Z'-substituents in the1,2,3,4,5,6-hexahydro-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocines and1,2,3,4,5,6-hexahydro-8-methoxy-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinesare known or are prepared by known methods. See, for example, Eddy andMay (reference cited above), Parfitt and Walters (J. Med. Chem., Vol.14, No. 7, 1971, pp. 565-568), May and co-workers (J. Med. Chem., Vol.12, No. 2, 1969, pp. 405-408), U.S. Pat. No. 3,320,265, British Pat.Nos. 1,299,699 and 1,299,700 and Netherlands Application No. 73/14758.

The following examples illustrate the invention. Structures of compoundsare inferred from reaction types. Confirmations of structures are madeby analyses of the elements, ultraviolet spectra, infrared spectra,nuclear magnetic resonance spectra and/or mass spectra. Courses ofreactions and homogeneities of products are ascertained by thin layerchromatography and/or gas-liquid chromatography. Melting and boilingpoints or ranges are uncorrected unless otherwise indicated.

EXAMPLE 1

A. A solution of3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine(Example 1 of U.S. Pat. No. 3,382,249, 11.0 g.) in acetic acid (50 ml.)was added with stirring and cooling (at 2.5°-5° C.) to a solution of redfuming nitric acid (155 ml.) and acetic acid (90 ml.). The temperaturewas allowed to rise slowly to room temperature. After being allowed tostand overnight the solution was purged with a stream of air, thenpartially evaporated (at 55°-60° C.) under reduced pressure to a yellowliquid (148 g.), to which was added a solution of sodium hydroxide (85g.) in water. A solution of the resulting product in chloroform waswashed with water, dried and concentrated, affording a red syrup (11.6g.). A solution of the red syrup in ether was filtered. Addition ofethereal hydrochloric acid to the filtrate and recrystallization of theproduct (10.3 g.) from ethanol afforded off-white crystals of3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-nitro-2,6-methano-3-benzazocinehydrochloride (7.2 g., m.p. 283°-284° C.). The free base was obtained asan orange syrup from the salt using sodium hydroxide and is the compoundof Formula II wherein Q' is cyclopropylmethyl, X is hydrogen, Y ismethyl, Z is hydrogen and Z' is methyl.

B. Iron powder (13.2 g.) was added portionwise to a solution of3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-nitro-2,6-methano-3-benzazocine(the free base product of part A of this example, 11.6 g.) water (35ml.), ethanol (60 ml.) and concentrated hydrochloric acid (3.66 ml.) andthe mixture was stirred under reflux. Sodium bicarbonate (5 g.) wasadded, the resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure. Ether and ethanol were added to theresidual yellow syrup, the resulting mixture was filtered and thefiltrate was concentrated. Hydrogen chloride was added to a solution ofpart (5.47 g.) of the resulting red syrup (10.4 g.) in ethanol.Recrystallization of the product (m.r. 303°-306° C.) from methanol-etherafforded off-white crystals of8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocinedihydrochloride (2.71 g., m.p. 314°-316° C.), the free base of which isthe compound of Formula I wherein Q is cyclopropylmethyl, R is hydrogen,R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' ismethyl.

C. A solution of the1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine (thefree base of which is the compound described as5,9-dimethyl-6,7-benzomorphan picrate and hydrochloride at J. Org.Chem., 24, 117 (1959); 40.4 g.) in acetic acid (320 ml.) was added to asolution of nitric acid (90%, 600 ml.) and acetic acid (400 ml.) withcooling (to 5°±1° C.) and stirring. The resulting mixture was allowed towarm to room temperature, poured onto ice (4500 ml.), basified withsodium hydroxide solution (35%) and extracted with ether. The etherextracts were dried and concentrated, affording a syrup (40.0 g.).Hydrogen chloride was added to a solution of the syrup in acetone.Recrystallization of the product (27.5 g., m.p. 252°-255° C.) fromethanol afforded as a white powder1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-nitro-2,6-methano-3-benzazocinehydrochloride (16.9 g., m.p. 266°-268° C.), the free base of which isthe compound of Formula II wherein Q' is hydrogen, X is hydrogen, Y ismethyl, Z is hydrogen and Z' is methyl.

D. Acylation of1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-nitro-2,6-methano-3-benzazocine(the free base of the product of part C of this example) withcyclopropanecarbonyl chloride provides1,2,3,4,5,6-hexahydro-3-cyclopropanecarbonyl-8-nitro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine,the compound of Formula VII wherein Q" is cyclopropanecarbonyl, X ishydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

E. Reduction of1,2,3,4,5,6-hexahydro-3-cyclopropanecarbonyl-8-nitro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine(the product of part D of this example) using iron and hydrochloric acidprovides1,2,3,4,5,6-hexahydro-3-cyclopropanecarbonyl-8-amino-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine,the compound of Formula VI wherein Q" is cyclopropanecarbonyl, R ishydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen andZ' is methyl.

F. Reduction of1,2,3,4,5,6-hexahydro-3-cyclopropanecarbonyl-8-amino-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine(the product of part E of this example) using lithium aluminum hydrideprovides8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine,which is identical with the free base product of part B of this example.

G. A solution of3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-8-methoxy-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine(the free base product of part A of Example 20 of U.S. Pat. No.3,372,165, 50.0 g.), tetrahydrofuran (500 ml.) and isopropyl alcohol(500 ml.) was added with stirring to liquid ammonia (about 1.5 l.) underreflux. Sodium (69.5 g.) was then added in small (about 1 g.) pieceswith continued stirring (during 1/2 hr.). After the blue color of thesolution had disappeared (about 1 hr. more), methanol (200 ml.) wasadded, the condenser was removed and the ammonia was allowed toevaporate overnight. The residual cloudy solution was diluted with waterand extracted with ether (three 300-ml. portions). The ether extractswere washed with water and brine, dried and concentrated, affording3-(cyclopropylmethyl)-1,2,3,4,5,6,7,10-octahydro-8-methoxy-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine(45.4 g.), part (10- and 20-g. portions) of which was converted into thehydrochloride salt using ethereal hydrogen chloride and concurrentlyhydrolyzed. Three recrystallizations of the combined salt portions frombenzene-methanol afforded white fine crystals of3-(cyclopropylmethyl)-1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-8-oxo-2,6-methano-3-benzazocinehydrochloride (about 8.5 g., m.p. 206°-208° C.), the free base of whichis the compound of Formula III wherein Q' is cyclopropylmethyl, X ishydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

H. A mixture of3-(cyclopropylmethyl)-1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-8-oxo-2,6-methano-3-benzazocinehydrochloride (the product of part G of this example, 1.0 g.),hydroxylamine hydrochloride (0.24 g.), ethanol (5 ml.) and pyridine (5ml.) was refluxed (for 3 hr.), diluted with water, basified with sodiumbicarbonate and extracted with chloroform. The chloroform extracts weredried and concentrated. Recrystallization of the residue from ethanolafforded3-(cyclopropylmethyl)-1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocine-8-oneoxime, the compound of Formula IV wherein Q' is cyclopropylmethyl, X ishydrogen, Y is methyl, Z is hydrogen and Z' is methyl. On larger scalethe product was obtained as off-white crystals (m.p. 190°-193° C.).

I. Acetic anhydride (1.02 g.) was added to a solution of3-(cyclopropylmethyl)-1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocin-8-oxime(the product of part H of this example, 2.2 g.) in acetic acid (20 ml.).Gaseous hydrogen chloride was bubbled through the solution, which wasthen refluxed (for 1 hr.) and stripped of solvents. Dilute hydrochloricacid (2 N) was added to the residue and the mixture was heated on thesteam bath (fpr 2 hr.), basified with aqueous ammonia and extracted withchloroform. The chloroform extracts were dried and concentrated.Ethereal hydrogen chloride was added to a solution of the residue inmethanol, affording8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocinedihydrochloride, the infrared spectrum of which showed that it wasidentical with the salt product of part B of this example.

EXAMPLE 2

A. A solution of1,2,3,4,5,6-hexahydro-8-methoxy-cis-6,11-dimethyl-2,6-methano-3-benzazocine(described as 2'-methoxy-5,9-dimethyl-6,7-benzomorphan at J. Org. Chem.,25, 986 (1960); 9.25 g.), tetrahydrofuran (130 ml.) and isopropylalcohol (130 ml.) was added with stirring to liquid ammonia (about 400ml.) under reflux. Sodium was then added in pieces (about 15) withcontinued stirring (during 1/2 hr.). After further stirring anddisappearance of the blue color (about 4 hr. more), methanol (40 ml.)was added and the mixture was warmed to room temperature and allowed tostand overnight. The residual colorless, cloudy solution was dilutedwith water (600 ml.) and extracted with ether (two 400-ml. portions).The ether extracts were washed with saturated salt solution, dried andconcentrated, affording1,2,3,4,5,6,7,10-octahydro-8-methoxy-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine(9.3 g.) as a yellow-brown oil.

Concentrated hydrochloric acid (8 ml.) was added to a solution of1,2,3,4,5,6,7,10-octahydro-8-methoxy-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine(21 g.) in acetone (50 ml.) and the mixture was kept cold (0° C.) forfive days. The crystalline product was collected in two crops. Each cropwas separately recrystallized from acetone-water and the products werecombined, affording off-white crystals of1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocin-8-onehydrochloride (11 g., 198°-201° C.), the free base of which is thecompound of Formula III wherein Q' is hydrogen, X is hydrogen, Y ismethyl, Z is hydrogen and Z' is methyl.

B. A solution of1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocine-8-onehydrochloride (the product of part A of this example, 2.0 g.),hydroxylamine hydrochloride (0.6 g.), pyridine (10 ml.) and ethanol (20ml.) was refluxed (for 2 hr.), then concentrated. The product wastriturated with isopropyl alcohol and dried, affording off-whitecrystals of1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocin-8-oneoxime hydrochloride (1.8 g., m.p. 237°-240° C.), the free base of whichis the compound of Formula IV wherein Q' is hydrogen, X is hydrogen, Yis methyl, Z is hydrogen and Z' is methyl.

C. Gaseous hydrogen chloride was bubbled through a mixture of1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocin-8-oneoxime hydrochloride (the product of part B of this example, 4.0 g.),acetic anhydride (2.0 g.) and acetic acid (15 ml.). The resulting redsolution was heated to reflux; the hydrogen chloride stream was stopped;and the solution was refluxed (for 3 hrs.), then concentrated. Asolution of the residual red syrup in dilute hydrochloric acid (6 N, 50ml.) was heated on a steam bath (for 1 hr.) and concentrated.Recrystallization of the resulting purple crystals from aqueous alcoholafforded light orchid crystals of8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocinedihydrochloride hydrate (4 g., m.p.> 280° C.), the free base of which isthe compound of Formula V wherein Q° is hydrogen, R is hydrogen, R' ishydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

D. A mixture of8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocinedihydrochloride hydrate (the product of part C of this example, 2 g.),cyclopropanecarbonyl chloride (3 g.), saturated sodium bicarbonatesolution (20 ml.) and chloroform (30 ml.) was stirred at ice temperature(for 1 hr.) and then at room temperature (for 1 hr.). The chloroformlayer was washed with saturated sodium bicarbonate solution andconcentrated, affording as a yellow oilN-(3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)cyclopropanecarboxamide(3.2 g.), the compound of Formula IX wherein Q' is cyclopropanecarbonyl,R is hydrogen, R" is cyclopropanecarbonyl, X is hydrogen, Y is methyl, Zis hydrogen and Z' is methyl.

E. A solution ofN-(3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine-8-yl)cyclopropanecarboxamide(the product of part D of this example, 3.8 g.) in tetrahydrofuran (30ml.) was added to a solution of diborane in tetrahydrofuran (1 M as BH₃,50 ml.) with cooling at ice temperature, then the mixture was heatedunder reflux (for 2 hr.). Dilute hydrochloric acid (5 N, 100 ml.) wasadded cautiously and the clear solution was concentrated under reducedpressure. The aqueous residue was washed with ether, basified withsodium hydroxide solution (35%) and extracted with chloroform. Thechloroform extracts were dried and concentrated to a red oil (3.2 g.). Asimilar reduction ofN-[3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine-8-yl]cyclopropanecarboxamide(5.8 g.) also afforded a red oil (5 g.). Crystallization of the red oilfrom isopropyl acetate afforded white crystals of3-(cyclopropylmethyl)-8-(cyclopropylmethylamino)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocinehydrochloride (m.p. 229°-232° C.), the free base of which is thecompound of Formula I wherein Q is cyclopropylmethyl, R is hydrogen, R'is cyclopropylmethyl, X is hydrogen, Y is methyl, Z is hydrogen and Z'is methyl.

EXAMPLE 3

A. Formic acid (10 ml.) was added dropwise with cooling (to 0° C.) toacetic anhydride (20 ml.) and the resulting solution was heated (to 50°C. for 1/4 hr.). A solution of8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine(the free base product of part B of Example 1, 6.7 g.) in formic acid(20 ml.) was added dropwise with cooling (to 0° C.). The resultingmixture was refrigerated overnight and stripped of solvents. The residuewas basified with sodium bicarbonate, then with concentrated aqueousammonia, and extracted with ether. The ether extracts were dried andstripped of ether, affordingN-(3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)-formamide (5 g.), thecompound of Formula VIII wherein Q' is cyclopropylmethyl, R is hydrogen,R" is formyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' ismethyl.

B. A mixture ofN-(3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)formamide(the product of part A of this example, 5 g.) and a solution of diboranein tetrahydrofuran (1 M as BH₃, 80 ml.) was refluxed (for 3 hr.),acidified with dilute hydrochloric acid (6 N) and stripped oftetrahydrofuran. The aqueous residue was washed with ether, basifiedwith sodium hydroxide and extracted with ether. The ether extracts weredried and stripped of ether. Ethereal hydrogen chloride was added to asolution of the product (3.5 g.) in ethanol, affording off-whitecrystals of3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-(methylamino)-2,6-methano-3-benzazocinedihydrochloride ethanolate hydrate (m.p.> 250° C.), the free base ofwhich is the compound of Formula I wherein Q is cyclopropylmethyl, R ishydrogen, R' is methyl, X is hydrogen, Y is methyl, Z is hydrogen and Z'is methyl.

EXAMPLE 4

A. A mixture of8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocinedihydrochloride hydrate (the product of part C of Example 2, 10 g.),acetic anhydride (20 ml.) and pyridine (100 ml.) was heated on a steambath (for 4 hr.) and stripped of solvents, affordingN-(3-acetyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)acetamide,the compound of Formula IX wherein Q" is acetyl, R is hydrogen, R" isacetyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

B. A mixture of the entire product of part A of this example and dilutehydrochloric acid (2 N):ethanol (1:1) was heated on a steam bath (for 2hr.), stripped of ethanol, cooled, basified with ammonia and extractedwith ether. The ether extracts were dried. The product crystallized fromthe ether solution and was recrystallized from ethyl acetate, affordingoff-white crystals of 3-acetyl-8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine(m.p. 208°-209° C.), the compound of Formula VI wherein Q" is acetyl, Ris hydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogenand Z' is hydrogen.

C. A mixture of3-acetyl-8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine(the product of part B of this example, 20 g.), formalin (35-40%, 25ml.), ethanol (180 ml.) and a catalytic amount of palladium-on-carbon(10%) was hydrogenated on a Parr apparatus (at 55° C.), then filtered.The filtrate was concentrated and the residue was dissolved in ether.The ether solution was dried and stripped of ether, affording as an oil3-acetyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine(17.7 g.), the compound of Formula VI wherein Q" is acetyl, R is methyl,R' is methyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' ismethyl.

D. A mixture of 3-acetyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine (the productof part C of this example, 17 g.) and concentrated hydrochloric acid(200 ml.) was refluxed (for 30 hr.), then concentrated. A mixture of theresidue and water was basified with concentrated aqueous ammonia andextracted with chloroform. The chloroform extracts were dried andconcentrated. The picrate salt of the product was recrystallized fromaqueous ethanol and freed of picric acid. The oxalate salt of theproduct was recrystallized three times from absolute ethanol and freedof oxalic acid, affording as an oil 1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine,the compound of Formula V wherein Q° is hydrogen, R is methyl, R' ismethyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

E. Cyclopropanecarbonyl chloride (4 ml.) was added dropwise withstirring and cooling to ice temperature to a mixture of1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocineoxalate (the oxalate salt product of part D of this example, 3.5 g.),chloroform (100 ml.) and dilute sodium hydroxide solution (1 N, 100ml.). Stirring was continued at room temperature (for 3hr.) and themixture was basified with sodium hydroxide. The chloroform layer waswashed with saturated sodium bicarbonate solution, dried and stripped ofchloroform, affording3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-dimethylamino)-2,6-methano-3-benzazocine (4 g.), thecompound of Formula VI wherein Q" is cyclopropanecarbonyl, R is methyl,R' is methyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' ismethyl.

F. A solution of3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine(the product of part E of this example, 4 g.) in tetrahydrofuran (20ml.) was added dropwise with stirring to a slurry of lithium aluminumhydride (2 g.) in tetrahydrofuran (70 ml.). The mixture was refluxed(for 3 hr.), then cooled. Saturated sodium potassium tartrate solutionwas added and the tetrahydrofuran layer was decanted and concentrated. Asolution of the residue in ether was washed with water, dried andconcentrated. Treatment of the residue with hydrogen chloride and tworecrystallizations of the product from ethanol afforded as an off-whitepowder3-cyclopropylmethyl-8-dimethylamino-cis-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocinedihydrochloride (m.p. 243°-246° C.), the free base of which is thecompound of Formula I wherein Q is cyclopropylmethyl, R is methyl, R' ismethyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

G. A mixture of1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-nitro-2,6-methano-3-benzazocinehydrochloride (the product of part C of Example 1, 14.2 g.), sodiumbicarbonate (9.5 g.), benzyl chloride (5.8 ml.) andN,N-dimethylformamide (90 ml.) was refluxed (for 4 hr.), then filtered,and the filtrate was concentrated. A solution of the residual syrup inether was filtered and acidified with ethereal hydrogen chloride. Tworecrystallizations of the product (18.2 g.) from ethanol afforded as anoff-white powder1,2,3,4,5,6-hexahydro-3-benzyl-6(eq),11(ax)-dimethyl-8-nitro-3-benzazocinehydrochloride (257°-258° C.), the free base of which is the compound ofFormula II wherein Q' is benzyl, X is hydrogen, Y is methyl, Z ishydrogen and Z' is methyl.

H. Reduction of1,2,3,4,5,6-hexahydro-3-benzyl-6(eq),11(ax)-dimethyl-8-nitro-3-benzazocinehydrochloride (the product of part G of this example) using iron andhydrochloric acid provides 8-amino-3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine, the compound of Formula Vwherein Q° is benzyl, R is hydrogen, R' is hydrogen, X is hydrogen, Y ismethyl, Z is hydrogen and Z' is methyl.

I. Reductive methylation of8-amino-3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine(the product of part H of this example) using formaldehyde and formicacid provides 3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine, thecompound of Formula V wherein Q° is benzyl, R is methyl, R' is methyl, Xis hydrogen, Y is methyl, Y is methyl, Z is hydrogen and Z' is methyl.

J. Debenzylation of3-benzyl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine(the product of part I of this example) by catalytic hydrogenation usingpalladium as catalyst provides1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine,which is identical with the product of part D of this example.

K. Acylation of1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine(the product of part D of this example) with cyclopropanecarbonylchloride provides 3-(cyclopropanecarbonyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-8-(dimethylamino)-2,6-methano-3-benzazocine, which isidentical with the product of part E of this example.

EXAMPLE 5

A. Isobutyryl chloride (8 ml.) was added dropwise to a solution of8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine(the free base of the product of part C of Example 2, 4 g.) andchloroform. Saturated sodium bicarbonate solution (50 ml.) was added andthe mixture was refluxed (for 2 hr.). The chloroform layer was washedwith saturated sodium bicarbonate solution, dried and concentrated,affording as a red oil N-(3-isobutyryl-1,2,3,4,5,6-hexahydro-6(eq), 11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)isobutyramide, the compoundof Formula IX wherein Q" is isobutyryl, R is hydrogen, R" is isobutyryl,X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

B. A solution ofN-(3-isobutyryl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)isobutyramide(the product of part A of this example, 5 g.), dilute hydrochloric acid(6 N, 200 ml.) and ethanol (100 ml.) was heated on a steam bath (for 3hr.), stripped of ethanol, washed with ether, basified with sodiumhydroxide and extracted with ether. The ether extracts were dried andconcentrated, affording8-amino-3-isobutyryl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine (about 4 g.), the compound ofFormula VI wherein Q" is isobutyryl, R is hydrogen, R' is hydrogen, X ishydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

C. A solution of8-amino-3-isobutyryl-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocine(the product of part (B) of this example, 4 g.) in tetrahydrofuran (50ml.) was added with stirring to a slurry of lithium aluminum hydride(2.5 g.) in tetrahydrofuran (100 ml.). Stirring was continued and themixture was refluxed (for 3 hr.), then cooled. Saturated sodiumpotassium bitartrate solution was added and the tetrahydrofuran layerwas decanted and concentrated. Ethereal hydrogen chloride was added to asolution of the residue in ethanol. Recrystallization of the resultingsolid from ethanol-ether and then from aqueous ethanol containingconcentrated hydrochloric acid afforded as an off-white powder 8-amino-1,2,3,4,5,6-hexahydro-3-isobutyl-cis-6,11-dimethyl-2,6-methano-3-benzazocinedihydrochloride (m.p.> 300° C.), the free base of which is the compoundof Formula I wherein Q is isobutyl, R is hydrogen, R' is hydrogen, X ishydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

EXAMPLE 6

A. A mixture of8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine(the free base of the product of part C of Example 2, 3g.), chloroform(80 ml.), saturated sodium bicarbonate solution (80 ml.) and propionylchloride (5 ml.) was stirred at room temperature (for 2 hr.). Thechloroform layer was dried and concentrated, affording as a red oilN-(3-propionyl-1,2,3,4,5,6-hexahydro-6-(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)-propionamide (4.2 g.),the compound of Formula IX wherein Q" is propionyl, R is hydrogen, R" ispropionyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

B. A mixture of the entire product of part A of this example, ethanol(50 ml.) and dilute hydrochloric acid (5 N, 25 ml.) was heated on asteam bath (for 1 hr.), then diluted with water. The resulting mixturewas washed with ether, basified with ammonia and extracted with ether.The ether extracts were washed with brine, dried and concentrated,affording as a red oil8-amino-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-3-propionyl-2,6-methano-3-benzazocine(3 g.), the compound of Formula VI wherein Q" is propionyl, R ishydrogen, R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen andZ' is methyl.

C. A solution of the entire product of part B of this example intetrahydrofuran was added with stirring to a slurry of lithium aluminumhydride (0.6 g.) in tetrahydrofuran (about 50 ml. in all). The mixturewas stirred under reflux (for 1 hr.), then cooled. Saturated potassiumsodium tartrate solution was added and the mixture was filtered. Thefiltrate was concentrated. Treatment of the residual red oil withhydrogen chloride and recrystallization of the product frommethanol-ether afforded as an off-white powder8-amino-cis-6,11-dimethyl-1,2,3,4,5,6-hexahydro-3-propyl-2,6-methano-3-benzazocinedihydrochloride sesquihydrate (m.r. 202°-207° C.), the free base ofwhich is the compound of Formula I wherein Q is propyl, R is hydrogen,R' is hydrogen, X is hydrogen, Y is methyl, Z is hydrogen and Z' ishydrogen.

EXAMPLE 7

A solution of8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine(the free base product of part B of Example 1, 4.4 g.), benzaldehyde(3.2 g.) and ethanol (100 ml.) was refluxed (for 2.5 hr.), then cooled.Sodium borohydride (1.0 g.) was added and the resulting solution wasstirred at room temperature (for 2 hr.), then concentrated. The residuewas diluted with hydrochloric acid (6%), washed with ether, basifiedwith sodium hydroxide and extracted with ether. The ether extracts werewashed with brine, dried and concentrated. Treatment of the residual redoil (5.2 g.) with hydrogen chloride and recrystallization of the productfrom ethanol afforded as a white powder3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-benzylamino-2,6-methano-3-benzazocinedihydrochloride (m.r. 233°-237° C.), the free base of which is thecompound of Formula I wherein Q is cyclopropylmethyl, R is hydrogen, R'is benzyl, X is hydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

EXAMPLE 8

A. A mixture of1,2,3,4,5,6,7,8,9,10-decahydro-6,11-cis-dimethyl-2,6-methano-3-benzazocin-8-onehydrochloride (the product of part A of Example 2, 5.12 g.), allylbromide (2.42 g.), sodium bicarbonate (3.36 g.) andN,N-dimethylformamide (about 50 ml.) was heated (at 140° C.) withstirring under nitrogen (for 1 hr.), then concentrated. The residue wasmixed with water, ether and saturated sodium bicarbonate solution. Theether layer was dried, treated with charcoal and concentrated. Additionof ethereal hydrogen chloride to a solution of the residue in ethanoland recrystallization of the product from ethanol-ether afforded3-allyl-1,2,3,4,5,6,7,8,9,10-decahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-onehydrochloride (4 g.), the free base of which is the compound of FormulaIII wherein Q' is allyl, X is hydrogen, Y is methyl, Z is hydrogen andZ' is methyl.

B. A mixture of3-allyl-1,2,3,4,5,6,7,8,9,10-decahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-onehydrochloride (the product of part A of this example, 1.7 g.),hydroxylamine hydrochloride (0.4 g.), pyridine (about 10 ml.) andethanol (about 20 ml.) was refluxed (for 2 hr.), then concentrated.Recrystallization of the residue from ethanol afforded3-allyl-1,2,3,4,5,6,7,8,9,10-decahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-oneoxime hydrochloride, the free base of which is the compound of FormulaIV wherein Q' is allyl, X is hydrogen, Y is methyl, Z is hydrogen and Z'is methyl.

C. A refluxing mixture of 3-allyl-1,2,3,4,5,6,7,8,9,10-decahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-one oxime hydrochloride (theproduct of part B of this example, 2.1 g.), acetic anhydride (0.7 g.)and acetic acid (about 30 ml.) was saturated with gaseous hydrogenchloride. The resulting red solution was stirred under reflux (for 2hr.) then concentrated. A mixture of the residue and dilutehydrochloride acid (2 N, 40 ml.) was heated on a steam bath (for 1 hr.),then concentrated. Crystallization of the residue from ethanol andrecrystallization of the product from ethanol afforded as an off-whitepowder8-amino-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocinedihydrochloride (m.p.> 270° C.), the free base of which is the compoundof Formula I wherein Q is allyl, R is hydrogen, R' is hydrogen, X ishydrogen, Y is methyl, Z is hydrogen and Z' is methyl.

EXAMPLE 9

A. Acetic anhydride (20 ml.) and pyridine (10 ml.) were added to aslurry of8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocinedihydrochloride (the product of part B of Example 1, 3 g.) in chloroform(100 ml.) with cooling at ice temperature. The resulting solution wasstirred with continued cooling (for 1 hr.), washed with sodiumbicarbonate solution, dried and concentrated, affording as a red oilN-(3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)acetamide,the compound of Formula VIII wherein Q' is cyclopropylmethyl, R ishydrogen, R" is acetyl, X is hydrogen, Y is methyl, Z is hydrogen and Z'is methyl.

B. Lithium aluminum hydride (0.5 g.) was added to a solution ofN-(3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)acetamide(the product of part A of this example, about 3 g.) in tetrahydrofuran(50 ml.). The slurry was refluxed (for 2 hr.), then cooled. Saturatedsodium potassium tartrate solution was added, the mixture was filteredand the filtrate was concentrated. An ether solution of the residue waswashed with water, dried and concentrated. Distillation of the residualred oil afforded as a yellow viscous oil3-(cyclopropylmethyl)-8-(ethylamino)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine(700 mg., b.r. 155°-160° C./0.03 mm.), the compound of Formula I whereinQ is cyclopropylmethyl, R is hydrogen, R' is ethyl, X is hydrogen, Y ismethyl, Z is hydrogen and Z' is methyl.

EXAMPLE 10

A. A mixture of8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocinedihydrochloride (the product of part B of Example 1, 4 g.), propionicanhydride (4 ml.), pyridine (8 ml.) and chloroform (80 ml.) was stirredovernight at room temperature. The resulting solution was washed withsodium bicarbonate solution, dried and concentrated, affording as ayellow oilN-(3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)propionamide(3.8 g.), the compound of Formula VIII wherein Q' is cyclopropylmethyl,R is hydrogen, R" is propionyl, X is hydrogen, Y is methyl, Z ishydrogen and Z' is methyl.

B. Lithium aluminum hydride (0.75 g.) was added slowly with cooling atice temperature to a solution ofN-(3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)propionamide(the product of part A of this example, 3.8 g.) in tetrahydrofuran (70ml.) and the resulting mixture was refluxed (for 1 hr.). Saturatedsodium potassium tartrate solution was cautiously added, the slurry wasfiltered and the filtrate was concentrated. Distillation of the residualoil afforded as an amber oil3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-8-(propylamino)-2,6-methano-3-benzazocine(2.0 g., b.r. 155°-160° C./0.05 mm.), the compound of Formula I whereinQ is cyclopropylmethyl, R is hydrogen, R' is propyl, X is hydrogen, Y ismethyl, Z is hydrogen and Z' is methyl.

EXAMPLE 11

A mixture of8-amino-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocinedihydrochloride (the product of part B of Example 1, 4 g.), butyricanhydride (4 ml.), pyridine (5 ml.) and chloroform (80 ml.) was stirredat ice temperature (for 2 hr.). The resulting solution was washed withsodium bicarbonate solution and concentrated, affording as a yellow oilN-(3-cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)butyramide(3.5 g.), the compound of Formula VIII wherein Q' is cyclopropylmethyl,R is hydrogen, R' is butyryl, X is hydrogen, Y is methyl, Z is hydrogenand Z' is methyl.

B. Lithium aluminum hydride (0.75 g.) was added cautiously with coolingat ice temperature to a solution ofN-(3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6(eq),11(ax)-dimethyl-2,6-methano-3-benzazocin-8-yl)butyramide(the product of part A of this example, 3.5 g.) in tetrahydrofuran (100ml.) and the resulting mixture was refluxed (for 3 hr.), then cooled.Saturated sodium potassium tartrate solution was added, the slurry wasfiltered and the filtrate was concentrated. Distillation of the residualoil afforded as an amber viscous liquid8-(butylamino)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocine(2.0 g., b.r. 161°-165° C./0.07 mm.), the compound of Formula I whereinQ is cyclopropylmethyl, R is hydrogen, R' is butyl, X is hydrogen, Y ismethyl, Z is hydrogen and Z' is methyl.

EXAMPLE 12

A. Benzyl chloride (250 g.) was added dropwise to a solution of3,4-diethylpyridine (262 g., Beilsteins Handbuch der Organischen Chemie,Vierte Auflage, Julius Springer, Berlin, 1935 p. 253) in isopropylalcohol (700 ml.). The resulting solution was refluxed (for 2 hr.), thenconcentrated under water pump vacuum. Benzene (250 ml.) was added to theresidue and the solution was concentrated again. The process wasrepeated with two further portions (250 ml. and 500 ml.) of benzene. Theresidue began to crystallize. Benzene (2250 ml.) was added, affording athick slurry of 1-benzyl-3,4-diethylpyridinium chloride.

B. A Grignard reagent prepared from magnesium (85.5 g.), benzyl chloride(407 g.) and ether (3020 ml.) was added to the slurry product of part Aos this example. Refluxing was maintained by the heat of reaction duringthe addition and was continued by applied heat after the addition (for1.5 hr.). The reaction mixture was quenched in ice-water containingammonium chloride (453 g.) and the quench was basified with aqueousammonia. The ether layer was washed with water and stripped of ether,affording 1,2-dibenzyl-3,4-diethyl-1,2-dihydropyridine (712 g.).

C. A solution of sodium borohydride (52 g.) in water (260 ml.) was addedto a solution of the entire product of part B of this example in ethanol(2 l.). The mixture was stirred (for 3.5 hr.) and allowed to standovernight at room temperature, then filtered. Water and ether were addedto the filtrate. The ether layer was washed with water, dried andconcentrated. Vacuum distillation of the residue (714 g.) produced twofractions (408.2 g. and 109.5 g.) which appeared to be only partiallyreduced. Therefore, dry sodium borohydride (42 g.) was added portionwiseto a solution of most (515 g.) of the combined two fractions in absoluteethanol (1 l.). The mixture was stirred at room temperature (for 6 hr.),then concentrated. Water and ether were added to the residue. The etherlayer was washed with water, dried and concentrated. Since the productstill appeared incompletely reduced, dry sodium borohydride (40 g.) wasadded to a solution of it in N,N-dimethylformamide (1 l.). The mixturewas allowed to stand overnight, diluted with water (2 l.) and extractedwith ether. The ether extracts were washed with water, dried andconcentrated. vacuum distillation of the residue afforded as a yellowliquid 1,2-dibenzyl-3,4-diethyl-1,2,5,6-tetrahydropyridine (Fraction II:b.r. 148° C./0.2 mm.-170° C./0.1 mm., 203 g.; Fraction III: b.r.154°-178° C./0.1 mm., mostly at 174° C., 172 g.).

D. A mixture of 1,2-dibenzyl-3,4-diethyl-1,2,5,6-tetrahydropyridine(Fraction III of part C of this example), hydrobromic acid (48%, 1350ml.) and acetic acid (50 ml.) was refluxed (for 22 hr.), thenconcentrated. The residue was treated with sodium hydroxide (35%) andextracted with benzene with warming and stirring. The benzene extractwas washed with water, dried and concentrated. Vacuum distillation ofthe residue (155 g.) afforded an orange syrup (Fraction I: b.r. 140°C./0.3 mm.-164° C./0.05 mm., 54.5 g.; Fraction II: b.r. 150°-184°C./0.05 mm., 72.3 g.). Oxalic acid (25 g.) was added to a solution ofFraction I of the orange syrup in ethanol (250 ml.), affording theoxalate salt (9.4 g., m.p. 213°-215° C.). Oxalic acid (32 g.) was addedto a solution of Fraction II of the orange syrup in ethanol (250 ml.),also affording the oxalate salt (24.9 g., m.p. 216°-221.5° C.). Amixture of most (29.9 g.) of the combined oxalate salts, dilute sodiumhydroxide (10%, 400 ml.) and toluene was swirled, then filtered.Concentration of the toluene layer afforded the free base as a yellowsyrup (22.6 g.). Treatment of the free base with hydrogen chlorideafforded the hydrochloride salt as a white solid (23.8 g., m.r.202°-205° C.). Recrystallization of part (2.5 g.) of the hydrochloridesalt from ethyl acetate affordedcis-6,11-diethyl-1,2,3,4,5,6-hexahydro-3-benzyl-2,6-methano-3-benzazocinehydrochloride (m.p. 210°-212.5° C.).

E. A mixture ofcis-6,11-diethyl-1,2,3,4,5,6-hexahydro-3-benzyl-2,6-methano-3-benzazocinehydrochloride (the hydrochloride salt product of part D of this example,8.9 g.), ethanol (100 ml.) and palladium-on-carbon (10%, 0.4 g.) washydrogenated with heating (at 50° C.) on a Parr apparatus, thenfiltered. Concentration of the filtrate and trituration of the residuewith ether afforded a white solid (6.0 g., m.r. 204°-211° C.).Recrystallization of part (all but 2.65 g.) of the white solid firstfrom isopropyl alcohol-ether and then from isopropyl alcohol affordedcis-6,11-diethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocinehydrochloride (m.r. 208.5°-211° C., about 3 g.). This hydrochloride saltpreparation was combined with two (14.5 g. and 15.4 g.) similarpreparations. The combined preparations were shaken with aqueous sodiumhydroxide and toluene, and the toluene layer was concentrated. Vacuumdistillation of the residue afforded the free base in three fractions(Fraction I: b.r. 78°-90° C./0.03 mm., 3.29 g.; Fraction II: b.r.90°-98° C./0.03 mm., 14.32 g.; Fraction III; b.p. 98° C./0.03 mm., 9.69g.).

F. Nitric acid (90%, 70 ml.) was added (during 1 hr.) to a solution ofcis-6,11-diethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (thefree base product of part E of this example, 22.66 g.) in acetic acid(75 ml.) cooled to ice temperature, then the mixture was allowed tostand overnight at room temperature. Ice (200 g.), water (50 ml.) andsodium hydroxide solution (35%, 125 ml.) were added. The resulting oilsolidified, affording in two crops a nitrate salt (31.3 g., m.r.210°-214° C.; 0.8 g., m.r. 225°-230° C.). Part (21.8 g.) of the nitratesalt was shaken with sodium hydroxide solution (35%), water and ether.The ether layer was washed with water, dried and concentrated. Etherealhydrogen chloride was added to a solution of the resulting red syrup(16.4 g.) in ethanol (200 ml.). Recrystallization of the resulting firstcrop (11.0 g., m.r. 285°-286° C.) of crystals from isopropyl alcoholafforded in two cropscis-6,11-diethyl-1,2,3,4,5,6-hexahydro-8-nitro-2,6-methano-3-benzazocinehydrochloride (1.7 g., m.r. 293°-294° C.; 7.1 g., m.r. 288°-289° C.),the free base of which is the compound of Formula II wherein Q' ishydrogen, X is hydrogen, Y is ethyl, Z is hydrogen and Z' is ethyl.

G. A mixture ofcis-6,11-diethyl-1,2,3,4,5,6-hexahydro-8-nitro-2,6-methano-3-benzazocinehydrochloride (the product of part F of this example, 3.11 g.), sodiumbicarbonate (2.0 g.), N,N-dimethylformamide (25 ml.) andcyclopropylmethyl bromide (1.60 g.) was refluxed (for 1.5 hr.), thenfiltered. The solid washed with ethanol and the filtrate wasconcentrated. The residue was shaken with water and ether. The etherlayer was washed with water, treated with charcoal and concentrated.Ethereal hydrogen chloride was added to a solution of the residue (3.0g.) in ethanol (15 ml.), affording crystalline3-(cyclopyropylmethyl)-6(eq),11(ax)-diethyl-1,2,3,4,5,6-hexahydro-8-nitro-2,6-methano-3-benzazocinehydrochloride (2.4 g., m.r. 243°-245° C.), the free base of which is thecompound of Formula II wherein Q' is cyclopropylmethyl, X is hydrogen, Yis ethyl, Z is hydrogen and Z' is ethyl.

H. A mixture of3-(cyclopropylmethyl)-6(eq),11(ax)-diethyl-1,2,3,4,5,6-hexahydro-8-nitro-2,6-methano-3-benzazocinehydrochloride (the product of part G of this example, 2.4 g.), water (6ml.), ethanol (11 ml.), iron filings (2.3 g.) and concentratedhydrochloric acid (2 drops) was heated on a steam bath with stirring(for 7 hr.). Sodium bicarbonate (1.5 g.) was added and the mixture wasfiltered. The solid was washed with ethanol and the filtrate wasconcentrated. The residue was partitioned between water and chloroformand the chloroform layer was concentrated. Trituration of the resultingsyrup (3.6 g.) with ether afforded a yellow powder. Addition of etherealhydrogen chloride to a solution of the yellow powder in ethanol affordedcrystals in two crops (0.9 g., m.p. 237° C.; 0.9 g., m.r. 226°-234° C.).Combination and recyrstallization of the two crops from aqueous acetoneafforded also in two crops white crystals of8-amino-3-(cyclopropylmethyl)-cis-6,11-diethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocinedihydrochloride (m.r. 290°-292° C. and m.r. 287°-290° C., total of 1.04g.), the free base of which is the compound of Formula I wherein Q iscyclopropylmethyl, X is hydrogen, Y is ethyl, Z is hydrogen and Z' isethyl.

As stated above the compounds of Formula I are useful as stronganalgesics, which can be demonstrated by standard pharmacologicalprocedures readily carried out by technicians having ordinary skill inpharmacological test procedures. Thus, the test results for a particularcompound can be determined without extensive experimentation.

All of the compounds of Formula I of the examples were tested anddetermined to be active in the acetylcholine writhing test, a primaryscreening test for analgesia. In this test the ability of test compoundsto prevent acetylcholine-induced writhing in mice is determined. Thefollowing is an adaptation of the method of Collier and co-workers(Brit. J. Pharmacol. Chemother., 32, 295(1968)) by Anne K. Pierson. Anintraperitoneal injection of acetyl-choline (3.2 mg./kg.) causes mice toexhibit writhing, which is abdominal constriction, and sometimestwisting, followed by extension of the hind limbs. The mice are dosedwith the test compound plus vehicle or vehicle alone (controls) 20minutes prior to, and are observed for 2 minutes after, theacetylchloine injection. During the 2-minute observation period mice notresponding by writhing are scored protected and mice responding bywrithing one or more times are scored not protected. The mice are dosedorally (usually at 150-200 mg./kg.) or subcutaneously (usually at 75-100mg./kg.). Fifteen mice per does level are used. ED₅₀ values for activecompounds are calculated by probit analysis (C. I. Bliss, The Statisticsof Bioassay, Academic Press, New York, 1952) of quantal scores of testsat four or more appropriate dose levels. The following subcutaneous ED₅₀values for the compounds of Formula I of the examples were determined.

    ______________________________________                                        Compound of     ED.sub.50 Value (mg./kg.)                                     ______________________________________                                        Example 1B      0.80                                                          Example 2E      0.70                                                          Example 3B      0.44                                                          Example 4F      0.79                                                          Example 5C      1.5                                                           Example 6C      5.6                                                           Example 7       1.6                                                           Example 8C      2.5                                                           Example 9B      1.3                                                            Example 10B    1.2                                                            Example 11B    1.0                                                            Example 12H    1.3                                                           ______________________________________                                    

We claim: 1.1,2,3,4,5,6-Hexahydro-3-Q'-8RR"N-5-X-6-Y-11-Z-11-Z'-2,6-methano-3-benzazocinehaving the formula ##STR11## wherein: Q' is hydrogen, benzyl, propyl,isobutyl, neopentyl, allyl, 2-methyl-2-propenyl, 2-chloro-2-propenyl,cis-3-chloro-2-propenyl, cis-3-chloro-2-butenyl,trans-3-chloro-2-butenyl, propargyl, cyclopropylmethyl or(2,2-dichlorocyclopropyl)methyl;R is hydrogen or methyl; R" is formyl,acetyl, propionyl, butyryl, isobutyryl, benzoyl or cyclopropanecarbonyl;X is hydrogen, methyl or ethyl; Y is hydrogen, methyl, ethyl, propyl,allyl or phenyl; Z is hydrogen, methyl, ethyl or hydroxy; and Z' ishydrogen, methyl or ethyl;or an acid addition salt thereof.
 2. Acompound according to claim 1 wherein X is hydrogen and Z is hydrogen oran acid addition salt thereof.
 3. A compound according to claim 2wherein Y is methyl and Z' is methyl or an acid addition salt thereof.4. A compound according to claim 3 wherein R is hydrogen or an acidaddition salt thereof.
 5. A compound according to claim 4 wherein Q' iscyclopropylmethyl or an acid addition salt thereof.
 6. A compoundaccording to claim 5 wherein R" is formyl or an acid addition saltthereof.
 7. A compound according to claim 5 wherein R" is acetyl or anacid addition salt thereof.
 8. A compound according to claim 5 whereinR" is propionyl or an acid addition salt thereof.
 9. A compoundaccording to claim 5 wherein R" is butyryl or an acid addition saltthereof. 10.1,2,3,4,5,6-Hexahydro-3-Q"-8RR"N-5X-6-Y-11-Z-11Z'-2,6-methano-3-benzazocinehaving the formula ##STR12## wherein: Q" is formyl, acetyl or Q* whereinQ* is propionyl, isobutyryl, pivaloyl, acryloyl, 2-methylacryloyl,2-chloroacryloyl, cis-3-chloroacryloyl, cis-3-chlorocrotonoyl,trans-3-chlorocrotonoyl, propiolyl, cyclopropanecarbonyl or2,2-dichlorocyclopropanecarbonyl;R is hydrogen or methyl; R" is formyl,acetyl, propionyl, butyryl, isobutyryl, benzoyl or cyclopropanecarbonyl;X is hydrogen, methyl or ethyl; Y is hydrogen, methyl, ethyl, propyl,allyl or phenyl; Z is hydrogen, methyl, ethyl or hydroxy; and Z' ishydrogen, methyl or ethyl.
 11. A compound according to claim 10 whereinX is hydrogen and Z is hydrogen.
 12. A compound according to claim 11wherein Y is methyl and Z' is methyl.
 13. A compound according to claim12 wherein R is hydrogen.
 14. A compound according to claim 13 whereinQ" is cyclopropanecarbonyl.
 15. A compound according to claim 14 whereinR" is cyclopropanecarbonyl.
 16. A compound according to claim 13 whereinQ" is acetyl.
 17. A compound according to claim 16 wherein R" is acetyl.18. A compound according to claim 13 wherein Q" is isobutyryl.
 19. Acompound according to claim 18 wherein R" is isobutyryl.
 20. A compoundaccording to claim 13 wherein Q" is propionyl.
 21. A compound accordingto claim 20 wherein R" is propionyl.